Method of treatment based on polymorphisms of the KCNQ1 gene

ABSTRACT

The invention provides methods for the administration of compounds capable of prolonging a QTc interval and methods for predicting whether an individual is predisposed to such QTc prolongation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/167,136, filed 6 Apr. 2009, which is herebyincorporated here.

SEQUENCE LISTING

The sequence listing contained in the electronic file titled“VAND-0039-US_Seq_ID_(—)6-12-2014_Cleartxt” created Jun. 12, 2014,comprising 995 KB, is hereby incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates generally to the administration of antipsychotics,and more particularly, to the administration of antipsychotics based onan individual's KCNQ1 genotype.

2. Background

Prolongation of the electrocardiographic QT interval (the time betweenthe start of the Q wave and the end of the T wave) is referred to aslong QT syndrome (LQTS). LQTS may comprise a genetic component. In somepatients with LQTS, QT prolongation can be a chronic condition. In somepersons, LQTS may be induced by the administration of an activepharmaceutical ingredient that prolongs the QT interval.

An area of focus in the evaluation of drug safety is the effect ofnon-cardiac medications on the QT interval. It is thought that theprimary mechanism of action by which non-cardiac medications prolong theduration of the QT interval is through inhibition of the HumanEther-a-go-go related Gene (HERG) channel, a potassium channel directlyinvolved in ventricular repolarization. QT prolongation and itsrelationship to torsades de pointes arrhythmia has received increasedattention from regulatory authorities, resulting in warnings on thelabels of some antipsychotics.

Since the QT interval changes with changes in heart rate, the QTinterval is often measured as a corrected QT (QTc) interval. Any numberof formulas may be employed to calculate the QTc, including, forexample, the Fridericia formula (QTcF), the Bazett formula (QTcB), andthe Rautaharju formula (QTp), among others.

DNA variants in potassium voltage-gated channels, such as KCNQ1, havebeen identified to predispose patients to drug-associated “acquired”LQTS and are considered congenital LQTS genes.

The KCNQ1 gene encodes a protein for a voltage-gated potassium channelrequired for the repolarization phase of the cardiac action potential.The gene product can form heteromultimers with two other potassiumchannel proteins, KCNE1 and KCNE3. Mutations in the KCNQ1 gene areassociated with hereditary LQTS, Romano-Ward syndrome, Jervell andLange-Nielsen syndrome, and familial atrial fibrillation. The gene islocated in a region of chromosome 11 that contains a large number ofcontiguous genes that are abnormally imprinted in cancer and theBeckwith-Wiedemann syndrome.

KCNQ1 alpha-subunits coassemble with KCNE1 beta-subunits to formchannels that conduct the slow delayed rectifier K+ current (IKs)important for repolarization of the cardiac action potential. Mutationsin KCNQ1 reduce IKs and cause LQTS.

Antipsychotics, both typical and atypical, have been associated with anincrease in the duration of the QTc interval. A study comparing theeffect of several antipsychotics on the QTc duration showed thioridazineto be associated with the highest degree of QTc prolongation, followedby ziprasidone. Quetiapine, risperidone, olanzapine, and haloperidolwere also associated with a prolongation of the QTc interval. In thisstudy, minimum increase in QTc was observed when metabolic inhibitors ofthe CYP450 isoenzyme responsible for the metabolism of each respectivedrug, except for haloperidol, which resulted in a doubling of QTc withmetabolic inhibition.

As has been seen with other antipsychotics, iloperidone has beenobserved to have some effects on QTc duration. Iloperidone ismetabolized by CYP2D6. Metabolic inhibition by adding an inhibitor ofCYP2D6 increases the effect of iloperidone on the QTcF duration. Methodsfor the administration of iloperidone based on an individual's CYP2D6genotype are described in International Patent Application PublicationNo. WO2006039663, which is incorporated herein.

In addition to iloperidone, a number of other compounds are believed tobe capable of causing QT prolongation. These include amiodarone, arsenictrioxide, bepridil, chloroquine, chlorpromazine, cisapride,clarithromycin, disopyramide, dofetilide, domperidone, droperidol,erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl,mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine,sotalol, sparfloxacin, and thioridazine.

Other compounds, in addition to ziprasidone, are suspected of beingcapable of prolonging the QT interval, although such prolongation hasnot been definitively established. These include alfuzosin, amantadine,azithromycin, chloral hydrate, clozapine, dolasetron, felbamate,flecainide, foscarnet, fosphenytoin, gatifloxacin, gemifloxacin,granisetron, indapamide, isradipine, levofloxacin, lithium, moexipril,moxifloxacin, nicardipine, octreotide, ofloxacin, ondansetron,quetiapine, ranolazine, risperidone, roxithromycin, tacrolimus,tamoxifen, telithromycin, tizanidine, vardenafil, venlafaxine, andvoriconazole.

Individuals at risk of suffering LQTS are advised not to use still othercompounds, due to the possibility that they may prolong the QT interval.These include albuterol, amitriptyline, amoxapine, amphetamine,dextroamphetamine, atomoxetine, chloroquine, ciprofloxacin, citalopram,clomipramine, cocaine, desipramine, dexmethylphenidate, dobutamine,dopamine, doxepin, ephedrine, epinephrine, fenfluramine, fluconazole,fluoxetine, galantamine, imipramine, isoproterenol, itraconazole,ketoconazole, levalbuterol, metaproterenol, methylphenidate, mexiletine,midodrine, norepinephrine, nortriptyline, paroxetine, phentermine,phenylephrine, phenylpropanolamine, protriptyline, pseudoephedrine,ritodrine, salmeterol, sertraline, sibutramine, solifenacin,terbutaline, tolterodine, trimethoprim-sulfa, and trimipramine.

SUMMARY OF THE INVENTION

The invention provides methods for the administration of compoundscapable of prolonging a QTc interval and methods for predicting whetheran individual is predisposed to such QTc prolongation.

A first aspect of the invention provides a method of treating a patientwith a compound capable of prolonging the QT interval, the methodcomprising: determining at least a portion of the patient's KCNQ1 genesequence; and administering to the patient a quantity of the compoundbased on the patient's KCNQ1 gene sequence. In some embodiments, themethod further includes determining at least a portion of the patient'sCYP2D6 gene sequence.

A second aspect of the invention provides a method of determiningwhether an individual is predisposed to prolongation of the QTcinterval, the method comprising: determining at least a portion of anindividual's KCNQ1 gene sequence.

A third aspect of the invention provides a method of treating a patientwith a compound capable of prolonging the QT interval, the methodcomprising: characterizing an expression product of the patient's KCNQ1gene; and administering to the patient a quantity of the compound basedon the characterized expression product.

A fourth aspect of the invention provides a method of determiningwhether an individual is predisposed to prolongation of the QTcinterval, the method comprising: characterizing an expression product ofan individual's KCNQ1 gene.

The illustrative aspects of the present invention are designed to solvethe problems herein described and other problems not discussed, whichare discoverable by a skilled artisan.

DETAILED DESCRIPTION

As indicated above, the invention provides methods for theadministration of antipsychotics based on an individual's KCNQ1genotype. The sequence of wild type KCNQ1 (GenBank Accession No.AJ006345.1) is provided herein as SEQ. ID. 1.

As noted above, a large number of compounds are known or suspected to becapable of inducing QT prolongation in some individuals, includingindividuals not suffering from LQTS. Such compounds may includecompounds of Formula (1):

wherein:

R is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxyl,carboxyl, lower hydroxyketone, lower alkanol, hydroxyl acetic acid,pyruvic acid, ethanediol, chlorine, fluorine, bromine, iodine, amino,lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy,cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl,monoaklylaminocarbonyl, dialkylaminocarbonyl, formyl,

alkyl is lower alkyl, branched or straight and saturated or unsaturated;

acyl is lower alkyl or lower alkyloxy bonded through a carbonyl:

aryl is phenyl or phenyl substituted with at least one group, R₅,wherein each R₅ is, independently, hydrogen, lower alkyl, lower alkoxy,hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino,lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

heteroaryl is is a five- or six-membered aryl ring having at least oneheteroatom, Q₃, wherein each Q₃ is, independently, —O—, —S—, —N(H)—, or—C(H)═N—

W is CH₂ or CHR₈ or N—R₉;

R₁ is —H, lower alkyl, —OH, halo, lower alkoxy, trifluormethyl, nitro,or amino;

R₂ is C₂-C₅ alkylene, alkenylene (cis or trans), or alkynylene,optionally substituted by at least one C₁-C₆ linear alkyl group, phenylgroup or

where

Z₁ is lower alkyl, —OH, lower alkoxy, —CF₃, —NO₂, —NH₂, or halogen;

R₃ is lower alkyl or hydrogen;

R₇ is hydrogen, lower alkyl, or acyl;

R₈ is lower alkyl;

R₉ is hydroxy, lower alkoxy, or —NHR₁₀;

R₁₀ is hydrogen, lower alkyl, C₁-C₃ acyl, aryl,

X₁, X₂, and X₃ are, independently, —O—, —S—, ═N—, or —N(R₃)—, or X₁ andX₂ are not covalently bound to each other and are, independently, —OH,═O, —R₃, or ═NR₃; lower is 1-4 carbon atoms;

m is 1, 2, or 3; and

n is 1 or 2.

The compound may further include a compound of Formula (1) wherein:

R is —C(O)CH₂OH, —CH(OH)C(O)CH₂OH, —C(O)OH, CH(OH)CH₃, or C(O)CH₃;

R₁ is halo;

X₁ and X₂ are different and are ═O, —OH, ═N—, or —O—;

R₂ is C₂-C₄ alkylene or alkenylene;

R₃ is hydrogen, methyl, or ethyl;

X₃ is —O—; and

R is substituted as shown in Formula 1A

In a further embodiment, the compound may be iloperidone, which is alsoreferred to as1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone,as shown in Formula 1B:

Iloperidone is disclosed in U.S. Pat. Nos. 5,364,866, 5,658,911, and6,140,345, each of which is incorporated herein by reference.Metabolites of iloperidone may also be capable of prolonging a QTinterval. Metabolites of Iloperidone, e.g.,1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol,as shown in Formula 1C:

are described in International Patent Application Publication No.WO03020707, which is also incorporated herein by reference. Otheriloperidone metabolites include:1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone;1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone;4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol;4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxy-α-methylbenzenemethanol;1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone;and1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone.See U.S. Pat. No. 5,364,866 and International Patent ApplicationPublication Nos. WO9309276 and WO9511680, which are incorporated hereinby reference.

The DNA variants in KCNQ1 noted above were examined for correlation withiloperidone-induced QT prolongation. These single nucleotidepolymorphisms (SNPs) are shown in Table 1, below. The sequence of KCNQ1(GenBank Accession No. AJ006345.1) having a C to G mutation at position79764 is provided herein as SEQ. ID. 2.

TABLE 1 KCNQ1 SNPs Linked to Acquired LQTS Genbank Accession No.Position Mutation AJ006345.1 79764 C to G AJ006345.1 286414 G to AAJ006345.1 78927 A to C

Individuals from an earlier study of CYP2D6 genotypes and apredisposition to QT prolongation were genotyped at each of the KCNQ1SNPs above. 22 individuals had been given a dose of 8 mg of iloperidoneb.i.d., 30 had been given 12 mg b.i.d., and 22 had been given 24 mg q.d.

Results for the position 79764 SNP are shown below in Tables 2 and 3. Ascan be seen, individuals homozygous for the C>G polymorphism showed asignificantly greater increase in QTc interval following theadministration of iloperidone. In fact, the average QTc change inindividuals with the GG genotype was more than twice the change inindividuals with a non-GG genotype.

TABLE 2 79764 SNP Genotype and QTcF Change Following IloperidoneAdministration QTcF change Genotype n (msec) CC 13 10.38 CG 32 6.80 GG26 17.58

TABLE 3 79764 SNP Genotype and QTcF Change Following IloperidoneAdministration QTcF change Genotype n (msec) P value Non-GG 45 7.830.0008 GG 26 17.58

The results were similar when ziprasidone was administered at a dosageof 80 mg b.i.d. The QTc changes for each genotype are shown below inTables 4 and 5.

TABLE 4 79764 SNP Genotype and QTcF Change Following ZiprasidoneAdministration QTcF change Genotype n (msec) CC 5 8.30 CG 14 6.19 GG 615.32

TABLE 5 79764 SNP Genotype and QTcF Change Following ZiprasidoneAdministration QTcF change Genotype n (msec) P value Non-GG 19 6.750.084 GG 6 15.32

Similar results were observed for the 286414 position SNP, the resultsof which are shown below in Tables 6 and 7. Individuals homozygous forthe G>A polymorphism experienced average QTc increases more than doublethose experienced by individuals with a non-AA genotype.

TABLE 6 286414 position SNP Genotype and QTcF Change FollowingIloperidone Administration QTcF change Genotype n (msec) AA 32 12.50 AG18 3.15 GG 7 10.34

TABLE 7 286414 position SNP Genotype and QTcF Change FollowingIloperidone Administration QTcF change Genotype n (msec) P value AA 3212.51 0.0268 Non-AA 25 5.16

The 78927 position SNP also yielded similar results, shown below inTables 8 and 9. Again, individuals homozygous for the A>C polymorphismexperienced average QTc increases more than double those experienced byindividuals with a non-CC genotype.

TABLE 8 78927 position SNP Genotype and QTcF Change FollowingIloperidone Administration QTcF change Genotype n (msec) AA 10 7.21 AC31 9.19 CC 33 14.08

TABLE 9 78927 position SNP Genotype and QTcF Change FollowingIloperidone Administration QTcF change Genotype n (msec) P value Non-CC41 6.46 0.057 CC 33 14.08

As noted above, and as described in International Patent ApplicationPublication No. WO2006/039663, an individual's ability to metabolizeiloperidone may be predicted based on his/her CYP2D6 genotype. TheCYP2D6 gene is highly polymorphic, with more than 70 allelic variantsdescribed so far (see http://www.cypalleles.ki.se/).

The two most common polymorphisms within the CYP2D6 gene in Caucasianpopulations, CYP2D6G1846A and CYP2D6C100T, result in a “poormetabolizer” phenotype and thus higher circulating drug levels in theblood. The CYP2D6G1846A polymorphism represents a G to A transition atthe junction between intron 3 and exon 4, shifting the splice junctionby one base pair, resulting in frameshift and premature termination ofthe protein. The CYP2D6C100T polymorphism, also known as CYP2D6P34S,represents a C to T change that results in the substitution of a prolineat position 34 by serine. Both of these polymorphisms have beenassociated with reduced enzymatic activity for different substrates.

Interestingly, a relationship was found between the KCNQ1 polymorphismsabove and an individual's metabolizer status (i.e., “extensive,”“intermediate,” or “poor”), as predicted by whether the individual hasone or both of the CYP2D6G1846A and CYP2D6C100T polymorphisms.

Tables 10 and 11 below show CYP2D6 metabolizer status against QTcFmaxchange from baseline for individuals having GG and non-GG genotypes,respectively, at the KCNQ1 79764 position SNP.

TABLE 10 QTcF Change in Individuals Having KCNQ1 79764 Position SNPGenotype GG and Varying CYP2D6 Metabolizer Status CYP2D6 QTcFmaxMetabolizer Change Status n (%) (msec) Extensive 17 (65%) 16.4Intermediate  8 (31%) 18.1 Poor 1 (4%) 33.6

TABLE 11 QTcF Change in Individuals Having KCNQ1 79764 Position SNPGenotype Non-GG and Varying CYP2D6 Metabolizer Status CYP2D6 QTcFmaxMetabolizer Change Status n (%) (msec) Extensive 37 (82%) 8.3Intermediate  7 (16%) 3.1 Poor 1 (2%) 24.6

As can be seen, individuals who are GG at the 79764 SNP experiencegreater QTc prolongation than do individuals who are non-GG. Inaddition, within each group, and particularly among GG individuals,CYP2D6 metabolizer status is highly predictive of the relative degree ofQTc prolongation an individual will experience. Thus, an individual whois GG at the KCNQ1 79764 SNP and a CYP2D6 poor metabolizer may beadministered a lower dose of iloperidone or other QT-prolongingcompound, due to the individual's greater likelihood of experiencingmore severe QT prolongation. Alternatively, the individual may insteadbe administered a compound not known or suspected of causing QTprolongation.

In order to assess the CYP2D6 component to such prolongation, QTc changewas separately compared to the CYP2D6G1846A and CYP2D6C100Tpolymorphisms. These results are shown below in Tables 12 and 13. As canbe seen, individuals homozygous for the wild-type allele (G forCYP2D6G1846A and C for CYP2D6C100T) experienced less QT prolongationthan did individuals having one or two mutant alleles (A forCYP2D6G1846A and T for CYP2D6C100T).

TABLE 12 CYP2D6G1846A Polymorphism Compared to QTc Change FollowingIloperidone Administration QTcF change Genotype n (msec) P value GG 5211.1 AG 14 15.9 AA 2 41.6 GG 52 11.1 0.0594 Non-GG 16 18.5

TABLE 13 CYP2D6C100T Polymorphism Compared to QTc Change FollowingIloperidone Administration QTcF change Genotype n (msec) P value CC 5410.8 CT 14 16.9 TT 3 31.3 CC 54 10.8 0.0281 Non-CC 17 19.2

Tables 14 and 15 below show QTc changes in individuals grouped accordingto their KCNQ1 79764, CYP2D6G1846A, and CYP2D6C100T genotypes. Thisshows that individuals who were non-GG at KCNQ1 79764 and werehomozygous for the wild-type allele at the CYP2D6 loci (i.e., GG forCYP2D6G1846A and CC for CYP2D6C100T) experienced the least QTprolongation. Similarly, individuals who were GG at KCNQ1 79764 and hadone or two mutant alleles at the CYP2D6 loci (i.e., AG or AA atCYP2D6G1846A and CT or TT at CYP2D6C100T) experienced the greatest QTprolongation.

This may make it possible, for example, to manage the risk associatedwith the administration of compounds capable of prolonging the QTcinterval. Individuals possessing only the wild-type alleles at the KCNQ1and CYP2D6 loci may reasonably be expected to experience relativelylittle QTc prolongation while individuals possessing one or more mutantalleles may be expected to experience greater QTc prolongation, with theextent of prolongation increasing with an increasing number of mutantalleles. Individuals would then be administered a dosage of the compoundbased on his/her KCNQ1 and/or CYP2D6 genotypes or may be administeredanother compound instead that is not known or suspected of prolongingthe QTc interval.

The data in Tables 14 and 15 also suggest that KCNQ1 polymorphisms havea greater impact on QTc prolongation than do the CYP2D6 polymorphisms.This may provide greater detail in the risk management, testing, andtreatment methods above.

TABLE 14 QTcF Change Compared to KCNQ1 79764 and CYP2D6G1846A GenotypesFollowing Iloperidone Administration QTcF change (msec) KCNQ1 79764  7.6(n = 34) 9.6 (n = 6) non-GG KCNQ1 79764 19.5 (n = 15) 25.5 (n = 10) GGCYP2D6G1846A GG CYP2D6G1846A non-GG

TABLE 15 QTcF Change Compared to KCNQ1 79764 and CYP2D6C100T GenotypesFollowing Iloperidone Administration QTcF change (msec) KCNQ1 79764non-GG  7.4 (n = 35) 12.6 (n = 7)  KCNQ1 79764 GG 19.2 (n = 15) 23.5 (n= 10) CYP2D6C100T CC CYP2D6C100T non-CC

Additional KCNQ1 SNPs were examined for any correlation to apredisposition to QTc prolongation. Those SNPs are shown below in Table16. SNPs useful in the practice of the invention include those listedabove and in Table 16 below, and can be used singly or in anycombination of two or more.

TABLE 16 KCNQ1 SNP Genotypes and QT Prolongation FollowingAdministration of Iloperidone Affymetrix Lowest SNP No. rs_number¹Position² QTc change P value³ Allele A Allele B SNP_A-1861793 rs2348732764098 nonAA 0.110421 C T SNP_A-1905847 rs233446 2794201 nonAA 0.12044A C SNP_A-1905948 rs179428 2507085 nonAA 0.548076 A G SNP_A-2063010rs10832134 2459062 AA 0.613499 C T SNP_A-2070173 rs10832405 2605095nonAA 0.421724 G T SNP_A-2128672 rs10798 2826741 nonAA 0.149325 C TSNP_A-2138827 rs548566 2739224 AA 0.533236 A G SNP_A-2155585 rs2319152705591 nonAB 0.811901 A G SNP_A-2170993 rs170786 2707279 BB 0.609952 CT SNP_A-2176134 rs10766379 2782775 BB 0.149903 A G SNP_A-2203798rs8181588 2788117 nonBB 0.486341 A G SNP_A-2217853 rs179429 2507306 BB0.323283 C T SNP_A-2244304 rs7128926 2653320 AB 0.074244 C TSNP_A-2264175 rs6578283 2630151 BB 0.385571 A G SNP_A-2299737 rs1631772794989 AA 0.03059 A G SNP_A-2301145 rs163166 2781804 BB 0.147875 G TSNP_A-2305877 rs231916 2704944 nonAB 0.033582 A G SNP_A-4241656 rs2319072708706 nonBB 0.802946 A T SNP_A-4242308 rs2283208 2700435 AA 0.019908 AG SNP_A-4248246 — 2667398 nonAA 0.381774 C T SNP_A-4254887 rs2313482630257 nonBB 0.626472 A G SNP_A-4257005 rs16928297 2442696 AA 0.483607G T SNP_A-4281714 rs3852527 2783179 nonAA 0.197306 A G SNP_A-4288131rs231890 2732635 nonAB 0.573 C T SNP_A-4288827 rs10766218 2594657 AA0.357049 A G SNP_A-4301076 rs163171 2777641 nonAB 0.259187 C TSNP_A-4301585 rs9666537 2642440 nonBB 0.262343 C T SNP_A-4302062rs1971929 2729947 AA 0.611517 C G SNP_A-4302119 rs3852528 2783193 nonBB0.041388 A G SNP_A-1819033 rs151291 2731415 nonAA 0.260891 C TSNP_A-1824380 rs179409 2483882 AA 0.310425 C G SNP_A-1829337 rs2318732742118 nonAB 0.422393 C G SNP_A-1845199 rs2412058 2597705 AA 0.29063 CT SNP_A-1866128 rs12804445 2834275 BB 0.431295 A C SNP_A-2045452rs7942590 2590291 AA 0.7495 C G SNP_A-2078818 rs4430486 2741967 BB0.177528 C G SNP_A-2089816 rs10741669 2600056 nonAB 0.154721 C TSNP_A-2108877 rs10766212 2589728 AA 0.181241 A G SNP_A-2111327rs11517737 2481124 nonAB 0.612965 A G SNP_A-2115624 rs4930013 2818735 AB0.762452 G T SNP_A-2139714 rs4930149 2692602 AA 0.42212 A CSNP_A-2147212 rs11023096 2484579 BB 0.011594 A G SNP_A-2167641 rs79271292672108 nonAA 0.905521 A C SNP_A-2185200 rs231901 2687761 AA 0.399107 CT SNP_A-2188014 rs2237866 2486738 AA 0.016676 C T SNP_A-2199433rs12576156 2455394 nonAA 0.055461 C T SNP_A-2207071 rs163183 2801017nonBB 0.080842 A G SNP_A-2222217 rs231841 2680180 AB 0.041003 A CSNP_A-2248126 rs3819506 2484900 BB 0.043565 A G SNP_A-2279904 rs169285612672031 BB 0.222103 A G SNP_A-2279707 rs179407 2483474 nonBB 0.011184 CT SNP_A-2281097 rs1079714 2717317 nonBB 0.583124 C T SNP_A-2286096rs11023094 2483937 nonAB 0.158471 C T SNP_A-2306355 rs17744869 2780438nonBB 0.236986 C G ¹Official SNP nomenclature according to NCBI db SNPversion 126, May 2006. ²Chromosomal position based on the NCBI Build36.1, March 2006. ³P value of genotype having highest QT values versusall other genotypes.

Among the SNPs shown in Table 16, a genotype of TT at SNP_A-2279707(rs179407) was shown to accurately predict a predisposition to QTcprolongation. Therefore, an individual having a genotype of TT atSNP_A-2279707 (rs179407) may be predicted to be predisposed to QTcprolongation.

Table 17 below shows the results of a study of 174 individuals, each ofwhom was genotyped at the rs179407locus and their QT interval measuredfollowing the oral administration of 24 mg/day B.I.D. of iloperidone fora period of two weeks.

TABLE 17 QT Prolongation and Presence or Absence of a Genotype forSNP_A-2279707 (rs179407) Associated with a Predisposition to QTProlongation Change negative positive Threshold Low QT High QT Odds ppredictive predictive (msec) −test +test −test +test Ratio valuesensitivity specificity value value QT > 5 19 47 15 102 2.748936 0.00910.871795 0.287879 0.558824 0.684564 QT > 15 25 85 9 64 2.091503 0.08070.876712 0.227273 0.735294 0.42953 QT > 30 32 123 2 26 3.382114 0.10890.928571 0.206452 0.941176 0.174497

As can be seen in Table 17, an individual's KCNQ1 sequence at theSNP_A-2279707 (rs179407) locus is highly predictive of whether theindividual will experience QT prolongation following the administrationof iloperidone. For example, using the lowest threshold of a change inQTc interval (between baseline and the end of the second week) greaterthan 5 milliseconds (normal QTc intervals are between 0.30 and 0.44seconds for males and between 0.30 and 0.45 for females), 102 of thoseindividuals with a SNP genotype (test is considered positive if genotypefor SNP_A-2279707 (rs179407) is TT) associated with a predisposition toQT prolongation experienced QT prolongation while only 47 suchindividuals did not. Similarly, nearly seven times as many individuals(102) experiencing QT prolongation possessed a SNP genotype associatedwith a predisposition to QT prolongation as did not (15). This resultedin a sensitivity (probability that the individual will have a SNPgenotype associated with a predisposition to QT prolongation, given thathe/she experienced QT prolongation) of 0.87 and a specificity(probability that the individual will not have a SNP genotype associatedwith a predisposition to QT prolongation, given that he/she did notexperience QT prolongation) of 0.29, a negative predictive value(probability that the individual will not experience QT prolongation,given that he/she does not have a SNP genotype associated with apredisposition to QT prolongation) of 0.56, and a positive predictivevalue (probability that the individual will experience QT prolongation,given that he/she has a SNP genotype associated with a predisposition toQT prolongation) of 0.68.

The use of higher thresholds (i.e., QTs greater than 15 and 30milliseconds) yielded markedly increased negative predictive values(0.74 and 0.94, respectively). The associated decrease in positivepredictive values, from 0.68 for QTs greater than 5 milliseconds to 0.17for QTs greater than 30 milliseconds) suggests that additional factorsaffect more severe QT prolongation.

As the data in Table 17 show, an individual's KCNQ1 sequence at the SNPloci above may be used to predict whether an individual is predisposedto QT prolongation due to the administration of a compound capable ofprolonging the QT interval. That is, individuals having one or more SNPgenotype associated with a predisposition to QT prolongation mayreliably be predicted to experience a prolonged QT interval (i.e., a QTinterval prolonged by at least 5 milliseconds) following theadministration of a compound capable of prolonging the QT interval.Similarly, individuals not having any of the above SNP genotypesassociated with a predisposition to QT prolongation may reliably bepredicted to not experience severe QT prolongation (i.e., a QT intervalprolonged greater than 15 milliseconds) following the administration ofa compound capable of prolonging the QT interval.

Methods according to the invention may involve direct sequencing orgenotyping of an individual's KCNQ1 and/or CYP2D6 genes or thecharacterization of expression products of the genes. For example, asnoted above, the CYP2D6G1846A polymorphism results in prematuretermination of the CYP2D6 protein and the CYP2D6C100T polymorphismresults in the substitution of a proline at position 34 by serine.Either of these polymorphisms could be determined from the resultingproteins or RNA. Accordingly, the invention includes testing genesand/or their expression products.

The foregoing description of various aspects of the invention has beenpresented for purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed, and obviously, many modifications and variations arepossible. Such modifications and variations that may be apparent to aperson skilled in the art are intended to be included within the scopeof the invention as defined by the accompanying claims.

What is claimed is:
 1. A method of administering iloperidone or ametabolite thereof to a human individual, the method comprising:determining or having determined the individual's KCNQ1 genotype atposition 79764 of SEQ. ID. 1; and in the case that the individual'sKCNQ1 genotype at position 79764 of SEQ. ID. 1 is associated with anincreased risk of QT prolongation, administering to the individual afirst quantity of iloperidone or a metabolite thereof, and in the casethat the individual's KCNQ1 genotype at position 79764 of SEQ. ID. 1 isnot associated with an increased risk of QT prolongation, administeringto the individual a second quantity of iloperidone or a metabolitethereof, wherein the first quantity is less than the second quantity,wherein the KCNQ1 genotype associated with an increased risk of QTprolongation is GG at position 79764 of SEQ. ID. 1, and the KCNQ1genotype not associated with an increased risk of QT prolongation isnon-GG at position 79764 of SEQ. ID.
 1. 2. The method of claim 1,wherein the method comprises administering iloperidone to theindividual.
 3. The method of claim 1, wherein the method comprisesadministering a metabolite of iloperidone to the individual, wherein themetabolite is1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol.4. The method of claim 1, further comprising: Determining or havingdetermined at least a portion of the patient's CYP2D6 genotype, in thecase that the individual's CYP2D6G1846A genotype is AA or GA or theindividual's CYP2D6C100T genotype is TT or CT, and the individual'sKCNQ1 genotype is GG at position 79764 of SEQ ID NO: 1, administering tothe individual the first quantity of iloperidone or the metabolitethereof, and in the case that the individual's CYP2D6G1846A genotype isGG or the individual's CYP2D6C100T genotype is CC, and the individual'sKCNQ1 genotype is non GG at position 79764 of SEQ ID NO: 1,administering to the individual the second quantity of iloperidone orthe metabolite thereof.
 5. The method of claim 1, wherein the humanindividual is suffering from at least one condition selected from agroup consisting of: schizophrenia, including paranoid schizophrenia,catatonic schizophrenia, disorganized schizophrenia, undifferentiatedschizophrenia, and residual schizophrenia; schizoaffective disorder,depression, bipolar mania/depression, cardiac arrythmia, Tourette'sSyndrome, a psychotic disorder, including brief psychotic disorder, apsychotic disorder not otherwise specified, a psychotic disorder due toa general medical condition, and a substance-induced psychotic disorder;a delusional disorder, and schizophreniform disorder.
 6. A method oftreating a human individual with iloperidone or a metabolite thereof,the method comprising: characterizing an expression product of theindividual's KCNQ1 gene; and in the case that the characterizedexpression product corresponds to a KCNQ1 genotype of GG at position79764 of SEQ. ID. 1, administering to the individual a first quantity ofiloperidone or a metabolite thereof, and in the case that thecharacterized expression product corresponds to a KCNQ1 genotype ofnon-GG at position 79764 of SEQ. ID. 1, administering to the individuala second quantity of iloperidone or a metabolite thereof, wherein thefirst quantity is less than the second quantity.
 7. The method of claim6, further comprising: characterizing an expression product of theindividual's CYP2D6 gene; and determining whether the characterizedexpression product corresponds to a CYP2D6 polymorphism selected from agroup consisting of: CYP2D6G1846A and CYP2D6C100T.
 8. A method ofadministering iloperidone or a metabolite thereof to a human individualsuffering from long QT syndrome (LQTS), the method comprising:determining or having determined the individual's KCNQ1 genotype atposition 79764 of SEQ. ID. 1; and administering to the individual aquantity of the iloperidone or the metabolite thereof based on theindividual's KCNQ1 genotype at position 79764 of SEQ. ID. 1, wherein afirst quantity is administered to the individual in a case in which theindividual has a KCNQ1 genotype of GG at position 79764 of SEQ. ID. 1,and a second quantity is administered to the individual in a case inwhich the individual has a KCNQ1 genotype that is non-GG at position79764 of SEQ. ID.
 1. 9. The method of claim 8, further comprising:determining or having determined the individual's CYP2D6 genotype; anddetermining whether the individual's CYP2D6 genotype corresponds to aCYP2D6 polymorphism selected from a group consisting of: CYP2D6G1846Aand CYP2D6C100T.
 10. The method of claim 1, wherein the second quantityof iloperidone is 24 mg/day.
 11. The method of claim 6, wherein thesecond quantity of iloperidone is 24 mg/day.
 12. The method of claim 8,wherein the second quantity of iloperidone is 24 mg/day.
 13. The methodof claim 1, wherein the KCNQ1 genotype not associated with an increasedrisk of QT prolongation is CC or CG at position 79764 of SEQ. ID.
 1. 14.The method of claim 6, wherein the non-GG KCNQ1 genotype at position79764 of SEQ. ID. 1 is CC or CG.
 15. The method of claim 8, wherein thenon-GG KCNQ1 genotype at position 79764 of SEQ. ID. 1 is CC or CG.